Age-related macular degeneration (AMD) is the most common cause of acquired visual impairment in people over the age 60. AMD is a multifactorial, complex disorder associated both with environmental and genetic factors. All currently available treatment options, i.e., photodynamic therapy, laser photocoagulation, anti-VEGF compounds, are directed towards a temporary relief of some of the symptoms, mainly neovascularization. Despite concerted efforts over the last several years, the general knowledge of genetic determinants of AMD has not advanced substantially. The underlying hypothesis of this proposal is that increased susceptibility to AMD in individual cases results from a combination of subtle defects in many genes, i.e., from specific genotype(s). This proposal suggests a continuation of our current program directed towards deciphering the genetic cause of AMD by a combination of several approaches. These include: 1) Completing large, clinically and genetically well-characterized, cohorts of AMD patients and rigorously matched controls until reaching 2000 samples each; 2) Utilizing high-throughput screening methods, including recently introduced in our laboratory genotyping microarrays, to obtain data on genetic heterogeneity in these populations; 3) Correlating the large numbers (>4 million) of derived genotypes with specific (endo-)phenotypes in AMD by statistical analyses. Identification of genes, alleles, haplotypes, and genotypes underlying the AMD complex trait and understanding how these defects contribute to the development of macular degeneration has the potential to improve the quality of life of the affected individuals. Furthermore, it will enable the accurate identification of at-risk individuals before they develop the disorder, and has the potential to modify or prevent the devastating visual consequences of this disorder in future generations.